The etiology of HIV-related cardiovascular disease (CVD) specially in patients with a history of cocaine use is most likely multifactorial. This is highlighted by the finding that there is an increase in the incidence of CVD in individuals with a history of cocaine abuse who are not HIV-1 infected and a similar increase in CVD in HIV-1 infected individuals who have no history of drug use. In addition, marked vascular lesions have been documented in SIV infected juvenile rhesus macaques who have no history of drug use. Thus, the effects of cocaine and HIV-1 infection leading to CVD may operate by separate but overlapping pathways, synergistically accelerating the disease process. It is our working hypothesis that insult to the vascular endothelium is one of the factor that contributes to CVD in HIV-1 infection which is further exacerbated by the use of drugs such as cocaine. Our lab has been studying the biology of lymphoid-endothelial cell interaction in both humans and non-human primates (NHP) in a variety of settings including responses to viral infections. During this process we have acquired unique sets of reagents, tools, techniques, knowledge, experience and important preliminary data which we submit will aid in defining some of the mechanisms of pathogenesis of HIV and cocaine induced cardiac disease. Specifically, we propose to a) determine if HIV/SIV infected lymphoid cells show increased adherence to human and NHP microvascular endothelial cells (MVEC), respectively in the presence/absence of cocaine/catecholamines using both a static and dynamic culture system b) to define the effect of HIV/SIV infected lymphoid cells in the presence and absence of cocaine/catecholamine on the expression of select cell adhesion/costimulatory molecule (CAM/CSM's), cytokines and chemokines by human and NHP MVEC c) determine if the effect on CAM/CSM's, cytokines and chemokines requires a disease inducing lentivirus isolate d) determine if HIV infected lymphoid cells in the presence/absence of cocaine/catecholamine induces the breakdown of latency in latent CMV infected autologous aortic endothelial cells e) determine if co-culture of MVEC and autologous smooth muscle cells (SMC's) in the presence of cocaine/catecholamine alone, HIV/SIV infected autologous cells alone or in combination leads to SMC proliferation and remodeling and, f) determine whether interaction of HIV-1/SIV infected cells alone and/or in the presence of cocaine/catecholamine leads to the synthesis of metalloproteinases. We reason that such studies may provide unique insights on the relationship between the effects of cocaine and HIV infection in the pathogenesis of cardiovascular disease.